CD8 NK/T Cells and the Phylogeny of Cellular Immunity

CD8细胞毒性t淋巴细胞（CTL）识别并杀死主要组织相容性复合体（MHC） I类分子中表达抗原肽的靶标。因此，CTL在产生针对病毒和肿瘤的适应性免疫中起着至关重要的作用。自然杀伤细胞（NK）在先天免疫中发挥积极作用，通过检测和杀死病毒感染或肿瘤细胞，这些细胞表面MHC类分子下调，从而逃避适应性免疫系统的监视。越来越多的证据表明，一些免疫反应是由表达NK相关分子（CD8/NK t细胞）的CTL介导的。nk相关分子的复杂性和异质性及其在不同效应器（如CTL）中的表达的生物学和生理学意义尚不清楚。由于现在已经在包括青蛙在内的几种物种中确定，某些热休克蛋白（例如gp96或hsp70）可引发CD8 t细胞介导的针对其所伴随的抗原肽的适应性反应和先天免疫反应，因此首次探索这种假定的热休克产生免疫的祖先系统可能涉及表达nk相关分子的CTL的程度将具有重要意义。此外，在脊椎动物进化中占据关键地位的两栖动物中对NK/ t细胞的明确表征将支持CD8 NK/ t细胞代表连接先天和适应性免疫系统的重要进化步骤的假设。这一发现也证明了这种细胞在哺乳动物免疫中的重要性。最后，更好地了解爪蟾细胞介导的细胞毒性，可能对理解用于对抗病毒性病原体的免疫防御系统的假定缺陷具有重要意义，这些缺陷导致了两栖动物种群的全球下降。该项目的总体目标是利用我们的Xenopus模型，从进化的角度评估CD8 NK/T细胞在体外和体内对肿瘤、病毒和次要组织相容性抗原的先天和适应性免疫反应中的作用，并探索共同表达CD8和NK标记（CD8 NK/T细胞）的T细胞是细胞免疫的系统发育早期介质的想法。自然杀伤t淋巴细胞和细胞毒性t淋巴细胞是两种重要的免疫细胞类型，参与防御病毒感染和肿瘤。最近的研究表明存在一种具有中间特征的新型细胞类型。该研究计划的目标是从进化的角度来更好地理解这种新型免疫细胞在免疫防御癌症和病毒感染方面的作用，而不是使用青蛙爪蟾作为模型系统。

CD8 cytotoxic T-lymphocytes (CTL) recognize and kill targets that express antigenic peptides in the context of major histocompatibility complex (MHC) class I molecules. As such, CTL are crucially involved in the generation of adaptive immunity against viruses and tumors. Natural killer (NK) cells play an active role in innate immunity by detecting and killing virally-infected or tumor cells that have down-regulated their surface MHC class I molecules thereby escaping surveillance by the adaptive immune system. Growing evidence suggests that some immune responses are mediated by CTL expressing NK-associated molecules (CD8/NK T-cells). The biology and physiological significance of the complexity and heterogeneity of NK-associated molecules and their expression by different effectors (e.g. CTL) is unclear. Since it is now well established in several species, including frogs, that certain heat shock proteins (e.g. gp96 or hsp70) elicit both adaptive CD8 T-cell mediated responses against the antigenic peptides they chaperone, and innate immune responses, it will be of significance to explore, for the first time, the extent to which this putative ancestral system of hsp-generated immunity may involve CTL that express NK-associated molecules. In addition, an unequivocal characterization of NK/T-cells in an amphibian that occupies a pivotal position in the evolution of vertebrates would support the hypothesis that CD8 NK/T-cells represent an important evolutionary step that bridges the innate and adaptive immune systems. This finding would also attest of the importance of this cell type in immunity of mammals. Finally, a better knowledge of cell-mediated cytotoxicity in Xenopus may have crucial implication with respect to understanding putative defects in the immune defense systems used against those viral pathogens that are causing world-wide declines of amphibian populations. The overall goal of this project is to take advantage of our Xenopus model to assess, from an evolutionary perspective, the role of CD8 NK/T cells, both in vitro and in vivo, in innate and adaptive immune responses to tumor, viral, and minor histocompatibility antigens as well as to explore the idea that T-cells co-expressing CD8 and NK markers (CD8 NK/T-cells) are phylogenetically early mediators of cellular immunity. Natural killer and cytotoxic T-lymphocytes are two important types of immune cells involved in defense against virus infections and tumor. Recent studies suggest the existence of a novel cell type with intermediate characteristics. The goal of the research program is to use the frog Xenopus rather than mice as a model system to better understand the role of this new type of immune cell in immune defense against cancer and virus infections from an evolutionary perspective.